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瘦蛋白

位於7號人類染色體的基因
(重定向自肥胖荷尔蒙

瘦素德语英语: Leptin,西班牙语 : Leptina, 源于希腊语: λεπτός (leptos)“瘦”,又名瘦蛋白)是一種新近發現於白脂肪組織的蛋白質荷爾蒙,它的功用是调节脂肪储存,加快生物的新陈代谢,抑制食欲,控制体重[2]

Leptin
PDB解譯基於1ax8.
有效结构
PDB 直系同源检索:PDBe, RCSB
标识
代号 LEP; LEPD; OB; OBS
扩展标识 遗传学164160 鼠基因104663 同源基因193 GeneCards: LEP Gene
RNA表达模式
PBB GE LEP 207092 at tn.png
更多表达数据
直系同源体
物种 人类 小鼠
Entrez 3952 16846
Ensembl ENSG00000174697 ENSMUSG00000059201
UniProt P41159 P41160
mRNA序列 NM_000230 NM_008493
蛋白序列 NP_000221 NP_032519
基因位置 Chr 7:
127.88 – 127.9 Mb
Chr 6:
29.06 – 29.07 Mb
PubMed查询 [1] [2]
瘦素
PDB 1ax8 EBI.jpg
肥胖蛋白质瘦蛋白-E100的结构[1]
鉴定
标志 Leptin
Pfam(蛋白家族查询站) PF02024
Pfam宗系 CL0053
InterPro(蛋白数据整合站) IPR000065
SCOP(蛋白结构分类数据站) 1ax8

目录

簡介编辑

瘦素是一種由身體的脂肪組織所分泌的蛋白質荷爾蒙。编码基因obOb基因(或Lep基因)位於人類的第七號染色體上(其中Ob表示肥胖、Lep表示瘦素)。[3]人類瘦素是由167個胺基酸構成的蛋白質,大小為16 kDa。缺失ob基因的大鼠,食欲旺盛,体重显著增加,导致病态肥胖。它在身體的濃度使腦部知道現時身體上的脂肪數量,藉以控制食慾及新陳代謝的速率[4][5]。瘦素透過抑制下視丘食慾神經元並且刺激下視丘飽足神經元和孤立束核,造成飽足感。 [6]

合成位置编辑

瘦素主要是由白色脂肪組織的脂肪細胞製造。但其他像褐色脂肪組織胎盤合胞體滋胚層)、卵巢骨骼肌胃底腺較下面的區域)、乳腺上皮細胞骨髓[7]胃主細胞P/D1 cells[8]也會合成瘦素。

生理功能编辑

做為一種指示能量消耗的荷爾蒙,瘦素主要是由脂肪細胞分泌,其功能主要在於體細胞對於血糖、脂肪的使用與反應以及能量相關的內分泌系統調控。

作用位置编辑

瘦素直接作用於脊椎動物細胞膜上受體,此受體可於許多種類的細胞中發現,為第一型細胞因子受體[9]。瘦素也可間接與其他荷爾蒙互動,如胰島素升糖素胰島素樣生長因子生長激素糖皮質素等。在中樞神經中,瘦素也可以作用於下視丘的弓狀核,抑制食欲產生。

功能簡介编辑

瘦素的首要功能就是調控脂肪組織的含量,其作用主要功能以中樞神經與周圍體細胞分為以下二項:

  • 中樞神經系統中可抑制下視丘的食欲以調節食物攝取、運動等與能量平衡相關的活動。
  • 周邊組織中,瘦素主要的功能在於拮抗胰島素作用,包含抑制其分泌、促進體細胞使用脂肪作為代謝原料等,同時也對於身體進入青春期、免疫啟動,以及個體生長有關鍵作用。

瘦素受體编辑

瘦素受體在中樞神經中廣泛分布,其mRNA經過選擇性剪接具有六種亞型[10][11]

  • 主要產生內分泌反應的長型受體(ObRb)於下視丘以及海馬迴分布較多,此種亞型可調控下視丘腦細胞的代謝活性與神經內分泌功能,同時促進下視丘對食物攝取的抑制。
  • 短型的瘦素受體亞型(最常見者為ObRa,其餘為ObRc、ObRd、ObRf)則與瘦素由脈絡叢通過血腦屏障的過程有關。
  • 游離型的ObRe可以與血漿中的瘦蛋白結合,除調控此激素的血漿濃度,也可做為激素的結合蛋白以穩定血液中的瘦蛋白含量。

神經活性[12]编辑

在中樞神經中,瘦素主要透過JAK-STAT信號通路作用於下視丘孤束核海馬迴,其主要作用詳述如下:

  • 抑制下視丘外核飢餓神經元分泌體內神经肽Yneuropeptide Y(NPY)及刺鼠肽基因相关蛋白agouti-related peptide (AgRP)降低食欲(此神經元受損會導致厭食症)。
  • 使體內另一種荷爾蒙黑色素细胞刺激激素alpha-melanocortin stimulating hormone(α-MSH)的活躍程度增強
  • 刺激下視丘飽足神經元分泌pro-opiomelanocortin (POMC)與cocaine- and amphetamineregulated transcript (CART),降低食慾並促進體細胞運用脂肪代謝。(此區域受損會導致暴食症)
  • 於孤束核中促進glucagon-like peptide1(GLP-1)、cholecystokinin(CCK)作用,形成飽足感。
  • 邊緣系統抑制享樂性攝食的欲望。

在周邊,瘦素刺激交感神經活性以促進能量消耗,包含活化褐色脂肪產熱、運動等。

  • 有研究指出,瘦素可以減少β-amyloid與Tau蛋白的含量,因此對阿茲海默症可能具有舒緩作用,並可能影響其病生理。
  • melatonin會抑制瘦素分泌,但若同時有胰島素分泌則會促進分泌,因此睡眠時不會感到飢餓,同時睡眠剝奪生物體瘦素濃度會下降,容易造成肥胖。

內分泌编辑

瘦素對於體內營養狀態相當敏感,運動後、飢餓時瘦素的含量很低,會造成飢餓感、性激素低落、甲狀腺素與生長激素低落等,以減少體內養分的消耗。 當瘦素存在時,其作用乃是透過NPY、POMC、Kisspeptin等激素刺激下視丘分泌釋素,經門脈循環影響下視丘前葉,而導致內分泌對於營養狀態的修正。適度運動可以有效轉換營養狀態,從而維持體細胞對瘦素的反應活性,進食前運動效果更加顯著。 在胎兒肺部發育時,肺間質纖維母細胞會受肺泡上皮細胞釋放之PTHrP刺激而產生,回頭作用於第二型肺泡上皮,導致表面張力素的釋放。 脊椎動物性激素釋放與性腺成熟都需要瘦素刺激,若生物體長期處於飢餓導致瘦素含量過低,則可能因對下視丘的刺激不足導致女性停經。同時懷孕期胎盤也會產生瘦素,容易造成晨間孕吐等不適,但對胚胎發育有一定重要性。

免疫調節编辑

免疫學研究顯示,瘦素對於先天性免疫有一定程度的影響,包含促進嗜中性球趨化作用、活化巨噬細胞吞噬作用促進發炎,以及抑制調控T細胞、促進輔助T細胞後天免疫等功能。瘦素缺乏個體較容易發生感染,而瘦素過高的個體則較容易產生自體免疫。

骨質調控编辑

瘦素可以增加密質骨的含量,減少海綿骨含量,總體增加骨骼密度,此機制可能是透過交感神經傳入骨骼組織的纖維,或是經由神經內分泌系統達成。

血液中濃度编辑

瘦素會以游離形式或是與蛋白質結合的方式在血液中循環。[13]

生理變化编辑

瘦素濃度變化會與脂肪量呈指數關係,而非線性關係。[14][15]血液中的瘦素濃度在午夜和清晨之間較高,此現象可能意味著夜晚的食慾會被抑制。[16]而血液中瘦素濃度的晝夜節律可能會受用餐時間影響。[17]

在特定條件下编辑

就人類而言,很多情況下我們會發現,瘦素對於身體與大腦營養狀態的連結失去其嚴格調控的能力,且其濃度變化不再與脂肪濃度有相關:

在突變的情況下编辑

幾乎所有已知的瘦素突變都與極低(低至無法檢測)的免疫反應性瘦素血液濃度有關,而唯一的例外是在2015年1月發表的。它不具有功能性,但可用標準的免疫反應方法檢測出來。它被發現於一名兩歲半、極度肥胖的男孩,儘管他血液中瘦素濃度非常高,但是無法作用在瘦素受體上,所以在功能上是有所缺失的。[35]

疾病角色编辑

肥胖编辑

儘管瘦素用來降低食慾以作為循環信號,但由於身體內擁有體脂肪[36],所以肥胖個體在血液循環中通常表現出比正常體重個體更高的瘦素濃度。這些人因為逐漸地無法控制飢餓並調節其體重而表現出對瘦素的阻抗性,有點類似於第2型糖尿病患者對於胰島素的阻抗性。很多的解釋已經被提出來以解釋這一點現象。瘦素阻抗性的其中一個重要促成因子就是瘦素受體訊號傳遞的變化,特別是在下視丘弓狀核中,但是瘦素受體本身的缺乏或主要變化並不被認為是主要原因。其他解釋顯示還包括改變瘦素穿過血腦屏障(BBB)的路徑或是在發育過程中發生的改變。[37]

對瘦素在腦脊液(CSF)濃度的研究提供了瘦素減少穿過BBB以及在肥胖的人中觀察到降低到達身體中與肥胖有關的target(例如下視丘)的相關證據[38]。在人類中,已經觀察到肥胖者的CSF中瘦素濃度與血液相比低於正常體重者。其原因可能是高濃度的三酸甘油酯影響瘦素穿過BBB或由於瘦素轉運蛋白變得飽和[39]。雖然已知在肥胖者中可以瘦素從血漿轉移到腦脊液中的缺陷,但仍然發現他們的腦脊液瘦素濃度比瘦子多30%[40]。這些腦脊液中的高濃度瘦素並未能預防其肥胖。由於下視丘中瘦素受體的數量和質量在大多數肥胖者中似乎是正常的(根據瘦素mRNA研究推定)[41],這些個體的瘦素阻抗性可能是由後瘦素受體缺發而引起的,類似於第2型糖尿病中見到的後胰島素受體缺陷。[42]

當瘦素與受體結合時,它會活化許多細胞傳遞路徑。瘦素阻抗性可能由該路徑上的一個或多個部分中的缺陷所引起,尤其是JAK/STAT途徑。瘦素受體基因突變阻止STAT3活化的小鼠會變肥胖並表現出食慾過盛的狀態。藉由人工阻斷小鼠PI3K訊號傳遞,顯示PI3K途徑也可能參與瘦素阻抗性。PI3K路徑也被胰島素受體激活,因此是瘦素和胰島素一起作為能量恆定的一部分的重要區域。胰島素-pI3K途徑可以透過過極化使POMC神經元對瘦素變得不敏感。[43]

從出生開始攝取高果糖飲食與瘦素濃度的降低和瘦素受體mRNA在大鼠中的表現減少有關。大鼠長期食用果糖可以提高三酸甘油酯濃度,引發瘦素和胰島素阻抗性[44][45],然而,另一項研究發現瘦素阻抗性只有在飲食中高果糖與高脂肪的情況下才會發生。在飲食中。第三項研究顯示,給定小鼠高脂肪飲食情況下,高果糖會反轉了大鼠瘦素阻抗性。綜合上述的實驗,矛盾的結果意味著不確定瘦素阻抗性是否由高濃度的碳水化合物或脂肪引起,或者是同時增加兩者。[46]

已知瘦素與胰澱素相互作用,胰澱素是一種參與胃排空並產生飽足感的激素。當將瘦素和胰澱素同時使用於肥胖且對瘦素有阻抗性的老鼠時,觀察到老鼠的體重持續減輕。由於其明顯的反轉瘦素阻抗性的能力,胰澱素已經被建議作為肥胖的可能治療方法。[47]

有人提出,瘦素的主要角色是在濃度較低時作為飢餓訊號,以幫助維持脂肪儲存以便在飢餓時期存活,而不是用於防止暴飲暴食的飽足感訊號。瘦素濃度表示當動物有足夠的儲存能量來進行追求而不是獲取食物時。[48][49]這意味著肥胖者的瘦素阻抗性是哺乳動物生理學的正常部分,可能會帶來生存優勢。[50]瘦素阻抗性(與胰島素阻抗性和體重增加相結合)在給予老鼠無限制好吃且富含能量的食物後可見。[51]當動物恢復低能量飲食時,這種效果就會反轉。[52]這也可能具有演化的優勢:當食物充足時能夠有效儲存能量在時常缺乏食物的人群中是有利的。[53]

對減重的反應编辑

節食者,特別是那些體內脂肪細胞過多的節食者,其體內血液循環系統中瘦素濃度會下降。這種下降會導致甲狀腺活動、交感神經張力和骨骼肌能量消耗的可逆性降低,以及肌肉效率和副交感神經張力的增加。許多這些改變被重組瘦素的周邊靜脈給藥(通過靜脈進入手臂、手、腿或腳的靜脈)逆轉,以恢復飲食前的水平。[54]

血液循環中的瘦素濃度的下降也會改變參與食慾的調節、情緒和認知控制的大腦區域活動,這些區域可通過使用瘦素來反轉。[55]

瘦素在肥胖中的關節問題角色编辑

肥胖與退化性關節炎编辑

退化性關節炎和肥胖密切相關。肥胖是退化性關節炎發展的最重要的可預防因素之一。

最初,退化性關節炎和肥胖之間的關係被認為是完全根據生物力學認知的,根據該認知,過重導致關節磨損地更快。然而,今日我們認識到還有一種代謝成分可以解釋為什麼肥胖是退化性關節炎的危險因素,不僅對於負重的關節(例如,膝蓋),而且對於無法負重的關節(例如,手)[56]。因此,研究已經表明,減少體脂肪比起體重減輕本身,可以更大程度地減輕退化性關節炎。[57]該代謝成份與脂肪組織釋放促進發炎性的全身因子有關,其通常與退化性關節炎的發展密切相關。[58][59][60][61][62]

因此,脂肪因子和炎症介質的失調性產生,高脂血症和全身氧化壓力的增加是經常與肥胖相關的病症,其可以促進關節退化。此外,許多調節因子涉及脂肪組織、軟骨和其他關節組織的發育、維持和功能。這些因素的改變可能是肥胖與退化性關節炎之間的額外關聯。

瘦素與退化性關節炎编辑

脂肪細胞通過產生和分泌多種訊號分子與其他細胞相互作用,包括稱為脂肪因子的細胞訊號傳遞蛋白。某些脂肪因子可以被認為是激素,因為它們調節遠處器官的功能,並且其中一些已經特異性地參與關節疾病的病生理學。特別是有一種瘦素,近年來一直是研究關注的焦點。

與非肥胖個體相比,血液循環中的瘦素濃度與體重指數(BMI),更具體地與脂肪量呈現正相關,而肥胖個體在其血液循環中具有更高的瘦素濃度[63]。在肥胖個體中,增加血液循環中的瘦素濃度會引起不必要的反應,即由於對瘦素具有阻抗性而不會發生食物攝入減少或體重減輕。除了調節能量恆定的功能外,瘦素還在其他生理功能中發揮作用,例如神經內分泌傳訊,生殖,血管生成和骨頭形成。最近,瘦素已被認為是一種細胞因子,在免疫和發炎中具有多效性作用。[64][65][66][67]例如,瘦素可以在滑囊液中發現與體重指數相關,而瘦素受體表現在軟骨中為瘦素調節和許多炎症做反應,會損傷軟骨和其他關節組織。因此,瘦素已經成為將肥胖與退化性關節炎連結在一起的候選者,並且作為退化性關節炎的營養治療的主要目標。

與血漿中一樣,滑囊液中的瘦素濃度與BMI呈現正相關[68][69][70][71]。滑囊液的瘦素至少部分地在關節中合成,並且可以部分地起源於循環。瘦素已被證明是由軟骨細胞以及關節中其他組織產生的,包括滑膜組織,骨贅,半月板和骨頭[72][73][74][75][76][77]。位於膝關節外側的髕骨下脂肪墊也與滑膜和軟骨相鄰,最近被高度認為是瘦素的重要來源,以及其他促成退化性關節炎發病機制的脂肪因子和介質。[78][79][80][81]

隨著體重減輕,罹患退化性關節炎的風險可以降低。這種風險的降低部分地與關節負荷量減少有關,但也與脂肪量,中樞脂肪組織和與肥胖和全身因素相關的低水平炎症的減少有關。

越來越多的證據顯示瘦素作為退化性關節炎發病機制中的軟骨退化因子,並且作為該疾病進展的潛在生物標記,這顯示瘦素以及調節和訊號傳導機制可能是治療退化性關節炎的一種新穎且有希望的目標,尤其是那些肥胖患者。

肥胖個體更傾向於發展退化性關節炎,不僅是由於超重的機械負荷,而且還是由於可溶性因子的過量表現,即瘦素和促進發炎細胞因子,其造成關節發炎和軟骨破壞的問題。因此,由於代謝不足,肥胖個體處於改變狀態,這需要特定的營養治療使瘦素製造正常化並減少系統性低水平發炎症,以減少這些系統介質對關節健康的有害影響。

有營養補充劑和藥物製劑能夠針對這些因素並改善這兩種情況。

治療用途编辑

瘦素编辑

美國於2014年批准通過瘦素用於治療先天性瘦素缺乏和全身性脂肪失養症[82]

類瘦素-美曲普汀(重组人甲硫氨酰瘦蛋白)编辑

類瘦素美曲普汀(商品名Myalept,Myalepta)於2013年首次在日本獲批准,接著2014年2月在美國獲批准,到了2018年在歐洲也獲批准。在美國,它被指出可用於治療瘦素缺乏的併發症,以及與先天性或後天性全身性脂肪失養症相關的糖尿病高三酸甘油脂血症[83]而在歐洲,根據EMA(歐洲藥品管理局),除了調控飲食之外,還應使用美曲普汀來輔助治療脂肪失養症,此症的患者缺乏皮下的脂肪組織,然其他部位如肝臟和肌肉則會有脂肪堆積。該藥可用於患有全身性脂肪失養症(又稱Berardinelli-Seip syndrome和Lawrence syndrome)的成人和2歲以上的兒童,以及嘗試使用標準方法治療但失敗、患有部分脂肪失養症(包括Barraquer-Simons syndrome)的成人和12歲以上的兒童。[84]2019年4月1日起,英國國家健保局開始對所有患有先天性瘦素缺乏症的人(不分年齡)施行美曲普汀的治療。[85]

歷史编辑

自1950年以來,許多機構都會針對肥胖的小鼠進行研究,而直到1994年,Jeffrey Freidman才發現了瘦素。

編碼基因的鑑定编辑

1949年,在傑克遜實驗室,被拿來做研究的非肥胖小鼠群體意外地產生了肥胖的後代,顯示出調節飢餓和能量耗損的激素產生了突變。而具有同型合子突變(又稱ob突變(ob/ob))的小鼠,比起正常的小鼠,會大量的進食,並且極度肥胖。[86]到了1960年代,同樣在傑克遜實驗室,Douglas Coleman發現了導致肥胖和擁有類似ob突變表現型的第二個突變,並將其命名為糖尿病(db),因此,不論是ob/ob還是db/db,均會呈現肥胖的表現型。[87][88][89]而在1990年,Rudolph Leibel和Jeffrey M. Friedman發現了db基因的定位。[90][91][92]

與Coleman和Leibel的假設一致,Leibel和Friedman實驗室及其他研究小組隨後的幾項研究證實,ob基因編碼了一種新的激素,它在血液中循環,可以抑制ob型和野生型小鼠的食物攝取量以及體重,但在db型小鼠則不會產生同樣的作用。[93][94][95][96]

1994年,Friedman的實驗室發表了該基因的鑑定報告。[97]1995年,Jose F. Caro的實驗室提供了證據證明,小鼠ob基因的突變不會在人類中發生。此外,由於在肥胖的人中,ob基因的表現是增加而非減少的,因此顯示對瘦素的抗性是可能存在的。[98]根據Roger Guillemin的建議,Friedman將這種新的激素命名為leptin(瘦素),這個字是從希臘單字lepto衍伸來的,代表瘦的意思。[99][100]另外,瘦素是第一個被發現的脂肪細胞激素。[101]

1995年的後續研究證實db基因會編碼出瘦素受體,且它會表現在下視丘,而下視丘是一個已知會調節飢餓感和體重的大腦區域。[102][103][104][105]

了解科學史编辑

Coleman和Friedman因為發現了瘦素,獲得了許多獎項,包括Gairdner Foundation International Award(2005),Shaw Prize(2009)[106],Lasker Award[107], BBVA Foundation Frontiers of Knowledge Award[108]和King Faisal International Prize[109]。 然而,Leibel卻沒有得到同等程度的認可,因為他在Friedman發現基因後所發表的科學論文中並沒有被列為共同作者。有許多人對於Friedman遺漏Leibel以及其他也應該被列為共同作者的人做出了各種各種不同的猜測,而這些猜測也被放在許多出版物中,其中包括Ellen Ruppel Shell在2002年發表的著作The Hungry Gene[110][111]

瘦素的發現也記錄在一系列書籍中,包括 Robert Pool所寫的Fat: Fighting the Obesity Epidemic[112]、Ellen Ruppel Shell 所寫的The Hungry Gene,以及Gina Kolata所寫的Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting[113][114]。其中,Fat: Fighting the Obesity EpidemicRethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting回顧了Friedman實驗室中ob gene複製的過程,而The Hungry Gene則讓人們注意到Leibel對於發現ob基因突變的貢獻。

參看编辑

參考文献编辑

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